A paradigm shift in genetic predisposition to colorectal cancer: the impact of germline multigene panel testing on diagnosis and management.

This review article focuses on hereditary colorectal cancer (HCRC) in the era of next-generation sequencing and multigene panel testing.

Key points:

• Germline predisposition: Germline predisposition accounts for an estimated 5–10% of all colorectal cancers. Large unselected genomic cohorts now show pathogenic or likely pathogenic germline variants in about 3.3–15.5% of colorectal cancer cases overall, with rates consistently above 15% in early-onset disease (diagnosis before age 50).
• Expanded gene spectrum: The use of broad multigene panels has expanded the recognized spectrum of hereditary colorectal cancer beyond classic Lynch syndrome. A substantial proportion of variants are found in non–Lynch syndrome genes, including high- and moderate-penetrance genes, especially those involved in homologous recombination deficiency pathways.
• Shift to precision medicine: This evolving genetic landscape is shifting clinical practice from a “single-syndrome” model (e.g., Lynch-only focus) toward individualized, gene-specific precision medicine. Management is increasingly guided by specific lifetime cancer risk profiles associated with each germline variant, rather than a one-size-fits-all hereditary CRC category.
• Essential changes in practice: The authors argue that two changes are now essential to fully capture clinical benefit:
  1. Universal germline genomic testing for all patients with early-onset colorectal cancer.
  2. More proactive cascade testing models for at-risk relatives, emphasizing healthcare-initiated contact rather than relying solely on patient-mediated family communication.
• Regional implementation differences: Implementation feasibility differs by region. While frameworks in Europe and North America are more developed, integration in Asia faces significant barriers, including infrastructure, health system organization, cultural factors, and resource constraints. The review highlights the need for region-specific strategies to incorporate genomic medicine into colorectal cancer care in Asian settings.